Integrative analysis of the ST6GALNAC family identifies GATA2-upregulated ST6GALNAC5 as an adverse prognostic biomarker promoting prostate cancer cell invasion

Meiqian Li; Zhihui Ma; Yuqing Zhang; Hanyi Feng; Yang Li; Weicong Sang; Rujian Zhu; Ruimin Huang; Jun Yan

doi:10.1186/s12935-023-02983-x

Integrative analysis of the ST6GALNAC family identifies GATA2-upregulated ST6GALNAC5 as an adverse prognostic biomarker promoting prostate cancer cell invasion

Cancer Cell Int. 2023 Jul 19;23(1):141. doi: 10.1186/s12935-023-02983-x.

Authors

Meiqian Li^#¹, Zhihui Ma^#^{2

3}, Yuqing Zhang^#⁴, Hanyi Feng⁵, Yang Li⁴, Weicong Sang⁴, Rujian Zhu⁶, Ruimin Huang^{7

8

9}, Jun Yan^{10

11

12}

Affiliations

¹ Model Animal Research Center, Medical School of Nanjing University, Nanjing University, Nanjing, China.
² Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
³ University of Chinese Academy of Sciences, Beijing, China.
⁴ Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
⁵ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
⁶ Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China. tzzhurj@163.com.
⁷ Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. rmhuang@simm.ac.cn.
⁸ University of Chinese Academy of Sciences, Beijing, China. rmhuang@simm.ac.cn.
⁹ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. rmhuang@simm.ac.cn.
¹⁰ Department of Laboratory Animal Science, Fudan University, Shanghai, China. yan_jun@fudan.edu.cn.
¹¹ Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China. yan_jun@fudan.edu.cn.
¹² Model Animal Research Center, Nanjing University, Nanjing, China. yan_jun@fudan.edu.cn.

^# Contributed equally.

Abstract

Background: ST6GALNAC family members function as sialyltransferases and have been implicated in cancer progression. However, their aberrant expression levels, prognostic values and specific roles in metastatic prostate cancer (PCa) remain largely unclear.

Methods: Two independent public datasets (TCGA-PRAD and GSE21032), containing 648 PCa samples in total, were employed to comprehensively examine the mRNA expression changes of ST6GALNAC family members in PCa, as well as their associations with clinicopathological parameters and prognosis. The dysregulation of ST6GALNAC5 was further validated in a mouse PCa model and human PCa samples from our cohort (n = 64) by immunohistochemistry (IHC). Gene Set Enrichment Analysis, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and drug sensitivity analyses were performed to enrich the biological processes most related to ST6GALNAC5. Sulforhodamine B, transwell, luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to examine the PCa cell proliferation, invasion and transcriptional regulation, respectively.

Results: Systematical investigation of six ST6GALNAC family members in public datasets revealed that ST6GALNAC5 was the only gene consistently and significantly upregulated in metastatic PCa, and ST6GALNAC5 overexpression was also positively associated with Gleason score and predicted poor prognosis in PCa patients. IHC results showed that (1) ST6GALNAC5 protein expression was increased in prostatic intraepithelial neoplasia and further elevated in PCa from a PbCre;Pten^F/F mouse model; (2) overexpressed ST6GALNAC5 protein was confirmed in human PCa samples comparing with benign prostatic hyperplasia samples from our cohort (p < 0.001); (3) ST6GALNAC5 overexpression was significantly correlated with perineural invasion of PCa. Moreover, we first found transcription factor GATA2 positively and directly regulated ST6GALNAC5 expression at transcriptional level. ST6GALNAC5 overexpression could partially reverse GATA2-depletion-induced inhibition of PCa cell invasion. The GATA2-ST6GALNAC5 signature exhibited better prediction on the poor prognosis in PCa patients than GATA2 or ST6GALNAC5 alone.

Conclusions: Our results indicated that GATA2-upregulated ST6GALNAC5 might serve as an adverse prognostic biomarker promoting prostate cancer cell invasion.

Keywords: GATA2; Metastasis; Prognostic biomarker; Prostate cancer; ST6GALNAC5.

Abstract

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